Objective Measures of Neural Processing of Interaural Time Differences.

Neurons in the medial superior olive (MSO) perform one of the most time sensitive computations in the brain. Situated in the mammalian brainstem just one synapse removed from the auditory nerve, MSO neurons encode the location of low-frequency sounds in the horizontal plane by detecting the simultaneous arrival times of auditory inputs driven from the two ears, a process termed ‘binaural coincidence detection’. Given that sounds travel at ∼34 cm ms−1, the physiologically relevant range of interaural time differences (ITDs) is sub-millisecond for humans and smaller animals. Consequently, the reliable encoding of ITDs requires extraordinary temporal precision that must be maintained at sound frequencies approaching ∼2 kHz, the limit of phase locking exhibited by excitatory inputs to the MSO in most mammals. At first glance, a sensory system so heavily dependent on temporal precision would seem a poor candidate for neuromodulation, especially neuromodulation of presynaptic release. Yet a study in this issue of The Journal of Physiology provides compelling evidence that presynaptic GABAB receptors modulate neurotransmitter release at synapses onto MSO neurons and that such modulation improves the resolution of binaural coincidence detection (Fischl et al. 2012). GABAB receptors are G-protein-coupled receptors that, when expressed presynaptically, act through a variety of potential mechanisms to inhibit release probability. How might this contribute to ITD detection? An important clue comes from an insightful study by Brenowitz et al. (1998), who asked how GABAB activation affects the reliability of high-frequency synaptic transmission. Recording from neurons in the chick nucleus magnocellularis, avian analogs of the input neurons to the mammalian MSO, the authors stimulated auditory nerve afferents to evoke trains of EPSCs. They observed that while GABAB receptor activation reduced EPSC amplitudes generally, at frequencies above 100 Hz short-term depression was dramatically reduced, rendering later EPSC amplitudes greater than un-modulated controls. Thus, the strength and reliability of high-frequency synaptic transmission was improved, presumably by preserving vesicles for later release. A subsequent study by Kuba et al. (2002) in the avian equivalent of the MSO showed that artificial reductions in release probability could sharpen ITD detection by narrowing the time window for suprathreshold summation of bilateral EPSPs. Do such mechanisms reside in mammalian MSO?Hassfurth et al. (2010) found functional and anatomical evidence that excitatory and inhibitory inputs express GABAB receptors in MSO neurons. This expression appeared to be developmentally regulated for excitatory inputs, as GABAB-mediated depression of EPSC amplitudes dropped to smaller, but still significant, levels in the 3 weeks following the onset of hearing at around postnatal day 12. In contrast, GABAB-mediated depression of IPSC amplitudes remained consistent across development. In this issue, Fischl and colleagues provide an elegant examination of the functional implications of GABAB receptor modulation in the MSO (Fischl et al. 2012). Recording from MSO neurons in slices, they confirmed the earlier finding that activation of GABAB receptors depresses individual EPSCs and IPSCs. In contrast to the Hassfurth study, they found that IPSC decay kinetics were slowed by GABAB activation at mature ages and that EPSC depression remained strong across development. Next, in a result reminiscent of the Brenowitz findings, the authors demonstrated that GABAB activation reduced the amount of depression within 50–200 Hz trains of PSCs, yielding trains with more stable amplitudes. Fischl and colleagues then simulated binaural ITDs in the slice using trains of bilateral synaptic stimuli to evoke EPSPs. The firing of MSO neurons was highly sensitive to these simulated ITDs. Upon addition of the GABAB agonist baclofen to the bath, ITD functions narrowed significantly. Conversely, when a GABAB antagonist was added, ITD functions widened. This latter result provides important confirmation that GABA can be released under physiological conditions (albeit in a brain slice), and even more importantly, GABA can achieve concentrations sufficient to modulate ITD detection. As conventional stimulation techniques do not permit separate stimulation of excitatory and inhibitory inputs to the MSO, ionotropic inhibitory receptors were blocked in these experiments. To circumvent this, the authors developed a model incorporating excitatory and inhibitory inputs driven by in vivo-like patterns. Simulations revealed that both the amplitude modulation of EPSCs and IPSCs and the kinetic slowing of IPSCs by GABAB modulation significantly sharpened ITD tuning in MSO neurons. Moreover, this sharpening persisted over a range of simulated sound intensities. Together, these results provide compelling evidence that GABAB receptors on presynaptic terminals in the MSO afford a mechanism for rapidly and reversibly sharpening the receptive fields of MSO neurons. When this mechanism comes into play is an exciting question for future studies. At present, the source of GABAergic input to the post-hearing MSO remains a mystery (the primary inhibitory inputs to MSO are glycinergic), but two likely possibilities present themselves. GABA release from an auditory source might be linked to sound intensity levels and provide a way to dynamically dampen highly active synapses. Alternatively, GABAergic inputs from a non-auditory centre might link receptive field modulation with attention or other behavioural states, possibly enabling the system to select between detecting weak auditory stimuli and precisely localizing strong ones. Getting to the bottom of this will probably require a combination of careful anatomy and electrophysiology. More broadly, the present results highlight the growing evidence that computations in the auditory brainstem are subject to modulation (e.g. Kotak et al. 2001; Magnusson et al. 2008). Given the highly dynamic nature of auditory stimuli, this is perhaps not as surprising as it once seemed. It does hint, however, that a rich repertoire of modulatory mechanisms awaits discovery.

1. Interaural level differences (ILDs), created by the head and pinna, have long been known to be the dominant acoustic cue for azimuthal localization of high-frequency tones. However, psychophysical experiments have demonstrated that human subjects can also lateralize complex high-frequency sounds on the basis of interaural time differences (ITDs) of the signal envelope. The lateral superior olive (LSO) is one of two pairs of binaural nuclei where the primary extraction of binaural cues for sound source location occurs. "IE" cells in LSO are inhibited by stimuli to the contralateral and excited by stimuli to the ipsilateral ear, and their response rate is therefore dependent on ILD. Anatomic specializations in the afferent pathways to the LSO suggest that this circuit also has a function in the detection of timing cues. We hypothesized that, besides ILD sensitivity, the IE property also conveys a sensitivity to ITDs of amplitude-modulated (AM) tones and could provide the physiological substrate for the psychophysical effect mentioned above. 2. In extracellular recordings from binaural LSO cells in barbiturate-anesthetized cats, response rate was a periodic function of ITDs of AM stimuli, i.e., all cells displayed ITD sensitivity. Binaural responses were smaller than responses to stimulation of the ipsilateral ear alone and were minimal when the envelopes in both ears were in-phase or nearly so. There was good correspondence between responses to ITDs and to dynamic interaural phase differences (IPDs), created by a difference in the envelope frequency to the two ears. Qualitatively, the responses were consistent with the outcome of an IE operation on temporally structured inputs. 3. To compare the relative importance of ILD and ITD, responses to combinations of the two cues were obtained. Despite robust ITD sensitivity in all binaural LSO cells encountered, the changes in response rate that would occur in response to naturally occurring ITDs were small in comparison with the changes expected for naturally occurring ILDs. The main limitation on ITD sensitivity was a steep decline in average discharge rate as the modulation frequency exceeded several hundred Hertz. 4. ITD sensitivity was also present to broadband stimuli, again with minimal rates occurring near 0 ITD. The sensitivity depended in a predictable fashion on the passband of filtered noise and was absent to binaurally uncorrelated noise bands. In response to clicks, ILDs interacted with ITD in a complicated fashion involving amplitude and latency effects. 5. Three low-characteristic frequency (CF) LSO cells were encountered that were IE and showed ITD sensitivity to the fine structure of low-frequency stimuli.(ABSTRACT TRUNCATED AT 400 WORDS)

Sound localisation is defined as the ability to identify the position of a sound source. The brain employs two cues to achieve this functionality for the horizontal plane, interaural time difference (ITD) by means of neurons in the medial superior olive (MSO) and interaural intensity difference (IID) by neurons of the lateral superior olive (LSO), both located in the superior olivary complex of the auditory pathway. This paper presents spiking neuron architectures of the MSO and LSO. An implementation of the Jeffress model using spiking neurons is presented as a representation of the MSO, while a spiking neuron architecture showing how neurons of the medial nucleus of the trapezoid body interact with LSO neurons to determine the azimuthal angle is discussed. Experimental results to support this work are presented.

1. Previous studies of the superior olive of echolocating bats suggest that the lateral superior olive (LSO) retains the same structure and function as in other mammals but that the medial superior olive (MSO) is different in structure and possibly also in function. The present study is an examination of this idea in Pteronotus parnellii, a bat that has a large and well-defined MSO. 2. Using pure tones presented via earphones, we obtained data on frequency tuning for 60 single units and 96 multiunits in LSO and 94 single units and 154 multiunits in MSO. Of these we also obtained binaural response characteristics from 55 single units in LSO and 72 single units in MSO. 3. LSO and MSO each have a complete tonotopic representation, arranged in a sequence similar to that of other mammals studied. However, in both LSO and MSO there is an expanded representation of the frequencies around 60 kHz, the main frequency component of the bat's echolocation call; there is another expanded representation of the range around 90 kHz, the third harmonic of the call. The expansion of these frequency ranges suggests that the functions of LSO and MSO in Pteronotus are related to echolocation behavior. 4. The binaural characteristics of cells in LSO were essentially the same as those seen in other mammals. Most LSO units (93%) were excited by the ipsilateral ear and inhibited by the contralateral ear. The responses of nearly all LSO units were completely suppressed when the sound level at the two ears was equal. 5. The binaural characteristics of cells in MSO were different from those in nonecholocating mammals. Most MSO units (72%) were excited by the contralateral ear but were neither excited nor inhibited by the ipsilateral ear. Of the remaining units, 21% were excited by the contralateral ear and inhibited by the ipsilateral ear, and only 6% were excited by both ears. 6. The temporal discharge patterns of units in MSO differed from the tonic response pattern seen in LSO. Most MSO units had phasic response patterns, with a few spikes at the onset or offset of the stimulus; the response often changed from ON to OFF depending on stimulus frequency. 7. The results support the idea that in evolution LSO has remained unchanged, whereas MSO has undergone adaptation. The function of LSO in Pteronotus seems to be identical to that in other mammals, i.e., analysis of interaural sound level differences to derive azimuthal location. The function of MSO in Pteronotus must be different from that in nonecholocating mammals.(ABSTRACT TRUNCATED AT 400 WORDS)

This study investigates the functional organization of the superior olivary complex of the mustached bat with classical transmission electron microscopy and postembedding immunocytochemistry for gamma-aminobutyric acid (GABA) and glycine antisera in semithin serial sections. The ultrastructure and distribution of terminal types in the lateral superior olive (LSO) and the medial nucleus of the trapezoid body (MNTB) closely resemble that of other mammals; the organization within the medial superior olive (MSO) differs significantly. The differences concern the relative proportion of putatively inhibitory boutons, which appear as symmetrical synapses with flattened vesicles on MSO somata. In the bat, inhibitory boutons comprised 75-100% of perisomatic boutons, a value identical to that observed in the LSO. These terminals most likely arise from the MNTB. In other species, putatively inhibitory terminals form a much smaller proportion of perisomatic boutons in MSO. This difference suggests that in the bat MSO excitatory input to cell somata is considerably reduced and outweighed by inhibitory input. This suggestion is corroborated by immunocytochemical data. Glycine-immunoreactive puncta encrust somata of LSO and MSO cells to a similar degree and in rather homogeneous patterns throughout these nuclei. Putatively GABAergic terminals are located mainly on distal dendrites of MSO and LSO cells. Regional variations in the density of GABA-immunoreactive puncta in LSO suggest that different tonotopic zones are under differential modulatory influence. Both the LSO and MSO of the mustached bat contain significant amounts of putatively inhibitory projection cells. Coexistence of both antigens was commonly observed in subsets of cells. Quantitative analyses of labeling patterns and comparisons with other mammals suggest that the mix of neurotransmitters in projection cells of LSO and MSO is phylogenetically flexible, and thus the details of the functions of ascending pathways are species specific. In contrast to other mammals, the bat MSO forms parallel output pathways with excitatory and inhibitory components. Data are discussed in relation to specialized physiological response features.

Interaural time difference (ITDs) are the most important cue to the location of sounds containing low-frequency energy (Wightman and Kistler 1992). ITDs are encoded centrally in the medial (MSO) and lateral (LSO) superior olives which transmit the code to the inferior colliulus (IC) (Batra et al. 1997; Goldberg and Brown 1969). Each ITD-sensitive neuron is characterized by its best ITD (BD), the one producing maximal discharge rate. It is a longstanding view that these neurons are conceptually arranged in an array with best frequency (BF) on one axis and BD on the other to form a labeled-line code. According to this model, the stimulus ITD corresponds to the BD (i.e. the label) of the most active neuron in the array (Jeffress 1948). The labeled-line model is challenged by physiological data from guinea pig (confirmed in cat and gerbil) showing that the distribution of BD is highly dependent on BF, and in general does not correspond to the range of naturally-occurring ITDs (Brand et al. 2002; Hancock and Delgutte 2004; McAlpine et al. 2001). Instead, best interaural phase (BP = BD × BF) is more nearly independent of BF, such that the steepest slopes of neural rate-ITD curves tend to occur near the midline. Because the slopes, not the peaks, align near the midline (where perceptual ITD acuity is finest), it has been suggested that ITD is encoded by the discharge rate itself rather than by the locus of maximal activity (McAlpine et al. 2001). Thus, ITD may be represented by a population rate code, in which the activity of many neurons pool to form monolithic ITD channels on each side of the brain, and the stimulus ITD may be inferred by comparing the relative activity of the two channels (van Bergeijk 1962; von Bekesy 1960). Though the physiological data suggest the existence of a rate code, analysis of its viability has barely begun (Marquardt and McAlpine 2001). Here, we demonstrate that a population rate code model can account for the dependence of perceived laterality on stimulus bandwidth.

Input from the medial nucleus of trapezoid body to an interaural level detector

Analytical description of coincidence detection synaptic mechanisms in the auditory pathway

This study reports simulations of recent physiological results from the gerbil medial superior olive (MSO) that reveal that blocking glycinergic inhibition can shift the tuning for the interaural time difference (ITD) of the cell (Brand et al., 2002). Our simulations indicate that the model proposed in the study by Brand et al. (2002) requires precisely timed, short-duration inhibition with temporal accuracy exceeding that described in the auditory system. An alternative model is proposed that incorporates two anatomic observations in the MSO: (1) the axon arises from the dendrite that receives ipsilateral inputs; and (2) inhibitory synapses are located primarily on the soma in adult animals. When the inhibitory currents are activated or blocked, the model cell successfully simulates experimentally observed shifts in the best ITD. The asymmetrical cell structure allows an imbalance between the ipsilateral and contralateral excitatory inputs and shifts the ITD curve such that the best ITD is not at zero. Fine adjustment of the best ITD is achieved by the interplay of somatic sodium currents and synaptic inhibitory currents. The shift of the best ITD in the model is limited to approximately 0.2 ms, which is behaviorally significant with respect to ITDs encountered in perceptual tasks. The model suggests a mechanism for dynamically "fine-tuning" the ITD sensitivity of MSO cells by the opponency between depolarizing sodium currents and hyperpolarizing inhibitory currents.

The auditory system uses three cues to decode sound location: interaural time differences (ITDs), interaural level differences (ILDs), and spectral notches (SNs). Initial processing of these cues is done in separate brainstem nuclei, with ITDs in the medial superior olive, ILDs in the lateral superior olive, and SNs in the dorsal cochlear nucleus. This work addresses the nature of the convergence of localization information in the central nucleus of the inferior colliculus (ICC). Ramachandran et al. (1999) argued that ICC neurons of types V, I, and O, respectively, receive their predominant inputs from ITD-, ILD-, and SN-sensitive brainstem nuclei, suggesting that these ICC response types should be differentially sensitive to localization cues. Here, single-unit responses to simultaneous manipulation of pairs of localization cues were recorded, and the mutual information between discharge rate and individual cues was quantified. Although rate responses to cue variation were generally consistent with those expected from the hypothesized anatomical connections, the differences in information were not as large as expected. Type I units provide the most information, especially about SNs in the physiologically useful range. Type I and O units provide information about ILDs, even at low frequencies at which actual ILDs are very small. ITD information is provided by a subset of all low-frequency neurons. Type V neurons provide information mainly about ITDs and the average binaural intensity. These results are the first to quantify the relative representation of cues in terms of information and suggest a variety of degrees of cue integration in the ICC.

With the exception of low‐frequency characteristic frequency (CF) units, the ipsilaterally evoked discharge of the majority of S‐segment cells can be inhibited with simultaneous stimulation of the contralateral ear. The contralateral inhibitory CF is usually identical to the ipsilateral excitatory CF. The width of the contralateral inhibitory tuning curve is similar to the width of the ipsilateral excitatory tuning curve. Partial inhibition of the ipsilaterally evoked discharge increases the interspike intervals and increases the variability of the discharge. Inhibition, like excitation, is tonically acting. The contralateral inhibitory input with equally intense tones (measured in terms of decibels above threshold) is either about as effective as the excitatory input or less effective, rarely more effective. The primary factor determining the spike output from S‐segment cells is not the absolute intensity level of the stimulus but rather the relative intensity difference of the stimulus at the two ears. [Work supported in part by National Institutes of Health, U. S. Department of Health, Education, and Welfare.]

Background/Objectives: Speech understanding in noise relies on both temporal fine structure (TFS) and temporal envelope (ENV) cues. While TFS primarily conveys interaural time differences (ITDs) at low frequencies, ENV cues can also support ITD processing, especially when TFS is unavailable or degraded. Expanding the ENV by increasing modulation depth has been proposed to improve speech perception, but its effects on spatial release from masking (SRM) and binaural temporal processing in normal-hearing listeners remain unclear. The goal of this study was to evaluate the effect of ENV enhancement on SRM in young adults with normal hearing and its influence on ITD sensitivity and interaural coherence (IC). Method: Thirty normal-hearing native Kannada speakers (19-34 years) participated. Speech stimuli consisted of Kannada sentences embedded in four-talker babble at -5, 0, and +5 dB signal to noise ratio (SNR). Target and masker were spatialized using head-related transfer functions at 0°, 15°, and 37.5° azimuths. Stimuli were presented with and without ENV enhancement (compression-expansion algorithm). Speech recognition scores were analyzed using generalized linear mixed models, and SRM was calculated as performance differences between co-located and spatially separated conditions. Cross-correlation analyses were performed to estimate ITDs and IC across SNRs. Result: ENV enhancement yielded significantly higher SRM values across all SNRs and spatial separations. Benefits were greatest at lower SNRs and wider target-masker separations. Cross-correlation analysis showed enhanced IC and more reliable ITD estimates under the expanded condition, particularly at moderate SNRs. Conclusions: Temporal ENV enhancement strengthens spatial unmasking and binaural timing cues in normal-hearing adults, especially under adverse listening conditions. These findings highlight its potential application in auditory rehabilitation and hearing technologies where ENV cues are critical.

The binaural cue decoding in the human auditory pathway occurs in the medial superior olive (MSO) and the lateral superior olive (LSO). The MSO is sensitive to interaural time difference (ITD), whereas the LSO is sensitive to interaural level difference as well as to ITD at low frequencies. Functional models of such organs have been presented previously [Pulkki and Hirvonen, Acta Acoustica united with Acoustica 95, 883–900 (2009)]. However, the outputs of those models are not as such applicable as the level of the output varies for a point-like broadband stimulus depending on the frequency and between the models. Here, a method is presented to combine the outputs of such models and an additional model of the MSO designed to decode directional cues based on broadband envelope time-shifts between the ear canal signals. Applicable cues are obtained by mapping the outputs into azimuth direction values following the idea of self-calibration, and by favoring the cue values suggesting more lateral directions. Furthermore, it is shown how the resulting directional cues can be applied to form a binaural activity map, and that the activity map corresponds to the human perception in several scenarios of psychoacoustical experiments.

Ipsilateral inhibitory responses in the cat lateral superior olive

A novel deep learning (DL) method is proposed for binaural sound source localization with low SNR. Firstly, the binaural sound signals are decomposed into several channels by using Gammatone filter. Secondly, the 4 feature parameters of Head-related Transfer Function, interaural time difference (ITD), interaural coherence (IC), interaural level difference (ILD), and interaural phase difference (IPD) are extracted. Thirdly, ITD and IC go through a Deep Belief Network (DBN) to determine the quadrant of the sound source and reduce the positioning range. Then, ITD, IC, ILD, and IPD go through a Deep Neural Network (DNN) to obtain the azimuthal angle within 90 degrees. Experimental results show that the proposed algorithm can solve the front-back confusion, and obtain a superior performance with lower complexity and higher precision under low SNR conditions.